Introduction

• Paraneoplastic syndromes (PNS) are defined as systemic disorders resulting from the presence of cancer, but NOT related to the size, location or metastasis of the tumor or to the physiological activities of the normal, mature tissue of origin.
• Paraneoplastic conditions result from production and release of substances (hormones, cytokines, peptides, growth factors, etc) that are not normally produced by the cell of origin of the tumor or that are being produced in an extreme amount.
• PNS occur distant to the tumor.
• Stimulation of immune response leading to auto-immunity may also occur.
• PNS may also occur as a result of proteins produced by normal cells in response to the tumor.
• The treatment of choice for any PNS is to treat the underlying neoplasia.
• Recurrence of PNS signal tumor recurrence.

Paraneoplastic syndromes

1. Hypercalemia

• The most common PNS seen in veterinary patients.
• PNS is the most common cause of hypercalcemia Hypercalcemia: overview in dogs (2/3 of hypercalcemia patients are found to have cancer).
• It corresponds to elevated ionized calcium Blood biochemistry: ionized calcium (biologically active form).
• Associated most often with lymphoma Lymphoma , apocrine gland (anal sac) Anal sac adenocarcinoma adenocarcinoma, and multiple myeloma Myeloma.
• Diagnostic findings: isosthenuria or hyposthenuria Urinalysis: specific gravity (renal tubular dysfunction), elevated urea Blood biochemistry: urea and creatinine Blood biochemistry: creatinine , low to normal serum phosphorus Blood biochemistry: phosphate (if no secondary renal failure), elevated parathyroid hormone-related protein (PTHrp) PTHrP assay.
• These tumors produce hypercalcemia via production of one or more of the following:
  • Parathyroid hormone-related peptide (PTHrP).
  • Interleukin 1-beta (previously osteoclast activating factor - OAF).
  • Prostaglandins.
  • Vitamin D or analogues.
  • Growth factors (TGF-beta).
  • Receptor activator of nuclear factor kappa-B ligand (RANK-L).
• Differential diagnosis: primary hyperparathyroidism Hyperparathyroidism (primary) , hypoadrenocorticism Hypoadrenocorticism , kidney disease, hypervitaminosis D, idiopathic, osteolysis, granulomatous disese, spurious.
• Initial treatment: rehydration and calciuresis (0.9% NaCl), chemotherapy if lymphoma or multiple myeloma, surgery if anal sac adenocarcinoma, symptomatic (anti-sickness, anti-acid, low-calcium diets).
• Further treatment: diuretics (furosemide Furosemide ), bisphosphonates (pamidronate - inhibits osteoclastic activity), calcitonin (inhibits bone resorption and increases calciuresis), prednisolone Prednisolone once diagnostics have been performed.

2. Hypoglycemia 

• Defined as fasting blood glucose <60 mg/dl in the presence of a non-islet cell tumor Blood biochemistry: glucose Hypoglycemia.
• Tumor types associated with PNS hypoglycemia:
  • Hepatoma Liver: neoplasia.
  • Hepatocellular carcinoma Liver: hepatocellular carcinoma.
  • Leiomyoma leiomyosarcoma Leiomyoma / leiomyosarcoma.
  • Lymphoma Lymphoma.
  • Plasmacytoid tumors.
  • Hemangiosarcoma Hemangiosarcoma.
  • Oral melanoma Skin: melanoma.
  • Mammary neoplasia Mammary gland: neoplasia.
• Clinical signs: weakness, ataxia, collapse, seizures.
• Produce hypoglycemia via:
  • Somatomedin production (insulin-like growth factors): some laboratories measure somatomedin blood levels. Serum insulin level in these patients is typically low to low-normal.
  • Upregulation of insulin receptors.
  • Increased insulin binding by M proteins (myeloma).
• Diagnosis:
  • Rule out other causes of hypoglycemia (eg sepsis secondary to GI tumor perforation, increased utilization of glucose, hypoadrenocorticism, liver failure).
  • Look for primary neoplasia.
• Acute treatment: slow IV administration of diluted dextrose followed by CRI, treatment of sepsis if appropriate.
• Long-term treatment: surgery or medical therapies according to tumor type.

3. Hematological abnormalities

• Anemia Anemia: blood loss :
  • Most cancer-related anemias are not paraneoplastic.
  • PNS anemia would include immune-mediated anemia Anemia: immune mediated hemolytic.
  • Diagnosis: in-saline agglutination, Coomb's test Direct Coombs' test , blood smear Blood smear preparation examination (sherocytosis, evidence of regeneration).
  • Differential diagnosis: anemia of chronic disease, blood loss anemia, microangiopathic hemolytic anemia, neoplastic infiltration of the bone marrow.
  • Treatment: specific to the tumor (surgery, chemotherapy), immunosuppressive treatment.
• Polycythemia Polycythemia: secondary :
• • Associated with renal tumors, nasal fibrosarcoma, lymphoma, hepatic tumors, pheochromocytoma Pheochromocytoma , transmissible venereal tumor Skin: transmissible venereal tumor.
  • Erythrocytosis induced via: neoplastic production of erythropoietin (EP) or EP-like hormone, renal hypoxia leading to increased EP release, upregulation of EP receptors, alterations in EP metabolism.
  • EP levels typically high.
  • Differential diagnosis: arteriovenous shunt, severe dehydration, hyperadrenocorticism, polycythemia vera.
  • Treatment: surgical removal of the tumor, phlebotomy.
• Thrombocytopenia Thrombocytopenia :
  • Immune-mediated Immune-mediated thrombocytopenia secondary to underlying neoplasia.
  • Most often associated with lymphoma.
  • Any underlying neoplasia may induce immune-mediated disease.
  • Differential diagnosis: disseminated intravascular coagulation Disseminated intravascular coagulation , sequestration, bone marrow infiltration, bleeding/consumption.
  • Treatment: specific to the tumor (surgery/chemotherapy), immunosuppressive treatment, plasma.
• Neutrophilic leukocytosis:
  • Increased WBC count Hematology: leukocyte (WBC) ; not leukemic, or circulating tumor cells.
  • Reported with lymphoma, renal carcinoma, primary lung tumor, rectal polyp, metastatic fibrosarcoma.
  • Mechanism may involve growth factor production by tumor cells;
  • G-CSF, GM-CSF, IL-3.
  • May involve tissue necrosis of tumor and release of inflammatory mediators systemically.
  • Not a clinically significant problem.
• Hypereosinophilia Hematology: eosinophil :
  • Associated with mammary tumors, leiomyosarcoma, T-cell lymphoma, fibrosarcoma.
  • Cause: production of GM-CSF, interleukins (IL-5, IL-13, IL-17), eotaxins.
  • Differential diagnosis: eosinophilic leukemia, hypereosinophilic syndrome.
  • Not a clinically significant problem.
• Lymphocytosis:
  • Reported in a dog with thymoma Thymoma.

4. Neurologic PNS

• Most neurologic problems related to cancer are due to direct effects of primary or neoplastic lesion in the CNS.
• PNS neurologic signs usually related to auto-immune stimulation:
  • Megaesophagus Megaesophagus /myasthenia with thymomas. Also reported with osteosarcoma, lymphoma, bile duct carcinoma Liver: neoplasia.
  • Polyneuropathies, polymyopathies.

5. Hypertrophic osteopathy (HO) 

• Clinically seen as lameness, reluctance to walk, swollen warm limbs Hypertrophic osteopathy.
• Involves one or multiple limbs.
• Periosteal new bone formation seen radiographically:
  • Starts at distal limb and progresses up.
• Associated with mass lesions in the thorax or abdomen. Reported with bladder rhabdomyosarcoma, esophageal tumor, malignant Sertoli cell tumor, renal transitional cell carcinoma, nephroblastoma.
• Mechanism not completely understood:
  • Involves neuro-hormonal input. Excess production of GHRH and/or VEGF may be involved.
  • Severing the vagus nerve resolves the condition.
  • Blood flow to distal limbs is increased which leads to the bony proliferation.
• Differential diagnosis: heartworms, cardiac disease, lung atelectasis Lung: atelectasis , pregnancy, abscess, granuloma, foreign bodies, pneumonia.
• HO may be the first sign of a neoplastic disease.
• Anti-inflammatory doses of prednisone may ease pain and swelling.
• Bisphosphonates may be beneficial.

6. Cancer cachexia

• Weight loss in the face of adequate caloric intake.
• Protein, carbohydrate, and lipid metabolism are affected by cancer cells. Excessive cytokine stimulations (THF-alpha, Il-1beta, Il-6) leads to insulin resistance, extensive lipolysis, and proteolysis of tissue stores.
• Diet higher in fat may help patient to maintain weight.
• Removing underlying neoplasia is best treatment, if possible.
• A plasmid-DNA-mediated approach utilizing growth-hormone-releasing hormone (GHRH) increase levels of insulin-growth factor 1 (IGF-1) and may represent a mechanism for attenuating cancer cachexia in dogs.

7. Fever

• In animals with no signs of infection, PNS fever may be diagnosed.
• Tumor cells may release pyrogens (IL-1, IL-6, TNF-alpha, interferons).
• Diagnosis by exclusion of other causes of fever.

8. Hyperviscosity

• Monoclonal gammopathy: excessive production of a monoclonal line of immunoglobulin-producing plasma cells or lymphocytes.
• Causative tumors: myeloma Myeloma , lymphoma Lymphoma , lymphocytic leukemia Chronic lymphoid leukemia.
• Clinical signs: ataxia, cardiac disease, seizures, bleeding, blindness due to retinal bleeding.
• Diagnosis: protein electrophoresis, Bence-Jones proteins in the urine.
• Treatment: chemotherapy to treat the underlying tumor.

9. Syndrome of inappropriate secretion of antidiuretic hormone (AD)

• Unrecognized in veterinary medicine. Associated with lung, head, neck cancers in humans.
• Clinical signs: fatigue, inappetence, confusion, seizures.
• Diagnostic findings: hyponatremia Blood biochemistry: sodium , serum hypo-osmolarity, hypernatriesis, urine hyperosmolarity.
• Differential diagnosis: heartworm disease, congenital hydrocephalus, granulomatous amoebic meningoencephalitis, chemotherapy agents (cyclophosphamide, vincristine), pulmonary or CNS infections.

10. Ectopic adrenocorticotropic hormone (ACTH) syndrome)

• Reported in primary lung tumors and one case of abdominal neuroendocrine tumor in dogs.
• Clinical signs: similar to Cushing's disease Hyperadrenocorticism.
• Diagnostic findings: abnormal dexamethasone suppression test High-dose dexamethasone suppression test.
• Physiopathology: secretion of ACTH, ACTH precursors, endorphins, encephalins, and melanocyte-stimulating hormone result in excessive production of steroids from the adrenal glands.
• Treatment: surgical (tumor removal) or medical (mitotane, ketoconazole).

11. Cutaneous

• Alopecia Skin: alopecia - overview :
  • Progressive nonscarring alopecia in cat with pancreatic carcinoma: acute, bilateral alopecia with ventral glistening.
  • A similar paraneoplastic syndrome has been reported in cats with bile duct carcinoma.
• Cutaneous flushing:
  • Has been reported in a dog with primary ling tumor and concomitant intrathoracic mast cell tumor.
  • Differential diagnosis: drug reaction, demodicosis Skin: demodectic mange , systemic lupus erythematous Systemic lupus erythematosus.
• Nodular dermatofibrosis:
  • Presentation: multiple, lowly growing cutaneous nodules on the limbs, head and trunk. Most commonly in middle-aged German Shepherds.
  • Associated with bilateral renal cysts or cystadenocarcinomas.
  • Autosomal dominance inheritance, exon 7 of the Birt-Hogg-Dube locus on canine chromosome 5.
  • Treatment: palliative with surgical removal of the nodules if impairing quality of life.
• Necrolytic migratory erythema:
  • Associated with glucagonomas.
  • Presentation: circinate and gyrate areas of erosive blistering and erythema, ulceration and crusting on footpads.
  • Differential diagnosis: diabetic dermatopathy, hepatocutaneous syndrome Hepatocutaneous syndrome.
  • Treatment: removal of the glucagonoma.
• Pemphigus vulgaris Skin: pemphigus vulgaris :
  • Intraepidermal bullae and erosions of the skin and oral mucosa.
  • Associated with mediastinal lymphoma and splenic sarcoma.
• Feminization syndrome/hyperestrogenism Skin: idiopathic male feminizing syndrome :
  • Associated with testicular tumors (Sertoli cell tumor Testicle: sertoli cell tumor ).
  • Bilateral asymmetric alopecia, hyperpigmentation, pendulous prepuce, gynaecomastia, galactorrhea, atrophy of the penis, bone marrow suppression.
  • Treatment: castration Castration.

Direct effects of neoplastic growth

Hematological

Further Reading

Publications

Refereed papers

• Recent references from PubMed and VetMedResource.
• Withers S S, Johnson E G, Culp W T et al (2015) Paraneoplastic hypertrophic osteopathy in 30 dogs. Vet Comp Oncol 13 (3), 157-165 PubMed.
• Turek M M (2003) Cutaneous paraneoplastic syndromes in dogs and cats: a review of the literature. Vet Dermatol 14 (6), 279-296 PubMed.
• Mariani C L, Shelton S B, Alsup C P (1999) Paraneoplastic polyneuropathy and subsequent recovery following tumor removal in a dog. JAAHA 35 (4), 302-305 PubMed.
• Ogilvie G K, Walters L, Salman M D et al (1997) Alterations in carbohydrate metabolism in dogs with nonhematopoietic malignancies. Am J Vet Res 58 (3), 277-281 PubMed.
• Bagley R S, Levy J K, Malarkey D E (1996) Hypoglycemia associated with intra-abdominal leiomyoma and leiomyosarcoma in six dogs. JAVMA 208 (1), 69-71 PubMed.
• Lainesse M F, Taylor S F, Myers S L et al (1996) Focal myasthenia gravis as a paraneoplastic syndrome of canine thymoma: improvement following thymectomy. JAAHA 32 (2), 111-117 PubMed.
• Sharkey L C, Rosol T J, Gröne A et al (1996) Production of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by carcinomas in a dog and a cat with paraneoplastic leukocytosis. J Vet Intern Med 10 (6), 405-408 PubMed.
• Beaudry D, Knapp D W, Montgomery T et al (1995) Hypoglycemia in four dogs with smooth muscle tumors. J Vet Intern Med 9 (6), 415-418 PubMed.
• Crow S E, Allen D P, Murphy C J et al (1995) Concurrent renal adenocarcinoma and polycythemia in a dog. JAAHA 31 (1), 29-33 PubMed.
• Hammer A S & Couto C G (1994) Complications in multiple myeloma. JAAHA 30 (1), 9-14 VetMedResource.
• Forrester S D & Fallin E A (1992) Diagnosing and managing the hypercalcemia of malignancy. Vet Med 87 (1), 26-39 VetMedResource.
• Keller E T (1992) Immune-mediated disease as a risk factor for canine lymphoma. Cancer 70 (9), 2334-2337 PubMed.
• Klebanow E R (1992) Thymoma and acquired myasthenia gravis in the dog - a case report and review of 13 additional cases. JAAHA 28 (1), 63-69 VetMedResource.
• Thompson J P, Christopher M M, Ellison G W et al (1992) Paraneoplastic leukocyctosis associated with a rectal adenomatous polyp in a dog. JAVMA 201 (5), 737-738 PubMed.
• Ross J T, Scavelli T D, Matthieson D T et al (1991) Adenocarcinoma of the apocrine glands of the anal sac in dogs: a review of 32 cases. JAAHA 27 (3), 349-355 VetMedResource.
• Braund K G (1990) Remote effects of cancer on the nervous system. Sem Vet Med Surg (Small Anim) 5 (4), 262-270 PubMed.

Other sources of information

• Bergman J P (2013) Paraneoplastic syndrome. In: Small Animal Clinical Oncology. Eds S J Withrow, D M Vail, R L Page & E G MacEwan. 5th edn. Chapter 5. Philadelphia: W B Saunders. pp 83-97.
• Ogilvie G K, Moore A S (2006) Anemia as a manifestation of malignancy. Compendium 8 (4), 10-11.
• Ogilvie G K, Moore A S (2006) Cachexia as a manifestation of malignancy. Compendium 8 (8), 9-11.
• Vasilopulos R, Mackin A (2003) Humeral hypercalcemia of malignancy: diagnosis and treatment. Compendium 25 (2), 129-136.
• Vasilopulos R, Mackin A (2003) Humoral hypercalcemia of malignancy: pathophysiology and clinical signs. Compendium 25 (2), 122-128.